Prostaglandin D2 (PGD2) is the inflammatory mediator produced and released in the largest amounts by mast cells activated by the binding of antigens with immunoglobulin E (NPL 1), and is considered to play an important role in the elucidation of allergic reactions. PGD2 is detected at high concentration in an asthmatic's bronchoalveolar fluid (NPL 2), and it was reported that bronchoconstriction was induced by prostaglandin D2 inhalation in asthmatic patients but not healthy subjects (NPL 3).
On the other hand, synthases that generate PGD2 are referred to as prostaglandin D synthases. Two different types, hematopoietic prostaglandin D synthase and lipocalin-type prostaglandin D synthase, are known to exist. PGD2 participates in the onset and exacerbation of various diseases, including allergies, and in the regulatory mechanisms of the body; therefore, pharmaceutical preparations that can ameliorate excess production are considered to be very effective in the treatment of various diseases.
Human hematopoietic prostaglandin D synthases (H-PGDS) are mainly distributed throughout the placenta, lung, fetus liver, lymph node, brain, heart, thymus, bone marrow, and spleen. Moreover, at the cellular level, they are reported to be expressed in microglia in the brain, megakaryocyte, and Langerhans cells in the skin; Kupffer cells in the liver; macrophages; and many antigen-presenting cells such as dendritic cells, mast cells, and Th2 cells.
Moreover, from the fact that H-PGDS are highly expressed in mast cells or inflammatory cells at nasal mucosa in allergic rhinitis, or nasal polyps in chronic sinusitis, it is thought that PGD2 produced by H-PGDS plays an important role in the onset and exacerbation of allergic diseases, such as asthma, rhinosinusitis, dermatitis, and chronic obstructive pulmonary disease (NPL4). Further, the expression of H-PGDS is confirmed in the necrosed part of skeletal muscle, in which the expression of H-PGDS does not generally occur (NPL5). For this reason, it is suggested that PGD2 produced by a hematopoietic prostaglandin D synthase participates in diseases accompanied by tissue damage, such as muscular dystrophy, amyotrophic lateral sclerosis, multiple sclerosis, ulcerative colitis, rheumatoid arthritis, and chronic obstructive arterial disease (NPL6).
Therefore, an H-PGDS inhibitor is expected to find application as a pharmaceutical preparation that is useful as an agent for preventing and/or treating diseases such as allergic disease and inflammatory disease in which PGD2 produced by a hematopoietic prostaglandin D synthase or metabolite thereof participates, and muscle necrosis and traumatic brain injury.
There are some reports on an H-PGDS inhibitor (for example, PTL 1 and 2), and Patent Literature 3 discloses an H-PGDS inhibitor having a structure similar to that of the compound of the present invention. In addition, piperazine compounds have been widely studied as useful pharmacological agents in addition to H-PGDS inhibitors.
Patent Literature 4 discloses as a hedgehog signaling inhibitor, a piperazine compound having a furyl carbonyl piperazine structure. Patent Literature 5 discloses a wide range of piperazine compounds as compounds that interact with potassium channels.
Patent Literature 6 discloses a urea compound having a piperazine ring as a compound useful for treating a disease in which fatty acid amide hydrolase participates.